Antibody drug conjugates of kinesin spindel protein (KSP) inhibitors with anti-CD123-antibodies

Abstract

The present application relates to novel binder drug conjugates (ADCs), to active metabolites of these ADCs, to processes for preparing these ADCs, to the use of these ADCs for the treatment and/or prophylaxis of diseases and to the use of these ADCs for preparing medicaments for treatment and/or prophylaxis of diseases, in particular hyperproliferative and/or angiogenic disorders such as, for example, cancer diseases. Such treatments can be effected as monotherapy or else in combination with other medicaments or further therapeutic measures.

The invention claimed is: 
     
       1. A conjugate of an antibody with one or more drug molecules of the formula below: 
       
         
           
           
               
               
           
         
         wherein 
         BINDER is an anti-CD 123 antibody which is a chimeric or humanized variant of the antibody 7G3 or 12F1 or is an antigen-binding fragment thereof; 
         L is a linker; 
         n is a number from 1 to 50; and 
         KSP is a compound of the formula (I) below:
 Formula (I): 
 
       
       
         
           
           
               
               
           
         
         wherein 
         R 1  is —H, -L-#1, -MOD or —(CH 2 ) 0-3 Z,
 wherein 
 Z is —H, —NHY 3 , —OY 3 , —SY 3 , halogen, —C(═O)—NY 1 Y 2  or —C(═O)—OY 3 , 
 Y 1  and Y 2  are independently of one another —H, —NH 2 , —(CH 2 CH 2 O) 0-3 —(CH 2 ) 0-3 Z′ or —CH(CH 2 W)Z′, 
 Y 3  is —H or —(CH 2 ) 0-3 Z′, 
 Z′ is —H, —NH 2 , —SO 3 H, —COOH, —NH—C(═O)—CH 2 —CH 2 —CH(NH 2 )COOH or —(CO—NH—CHY 4 ) 1-3 COOH, 
 W is H or OH, and 
 Y 4  is straight-chain or branched C 1-6  alkyl which is optionally substituted by —NH—C(═O)—NH 2 , or represents aryl or benzyl which are optionally substituted by —NH 2 ; 
 
         R 2  is —H, -MOD, —C(═O)—CHY 4 —NHY 5  or —(CH 2 ) 0-3 Z,
 wherein 
 Z is —H, halogen, —OY 3 , —SY 3 , —NHY 3 , —C(═O)—NY 1 Y 2  or —C(═O)—OY 3 , 
 Y 1  and Y 2  are independently of one another —H, —NH 2  or —(CH 2 ) 0-3 Z′, 
 Y 3  is —H or —(CH 2 ) 0-3 Z′, 
 Z′ is —H, —SO 3 H, —NH 2  or —COOH; 
 Y 4  is straight-chain or branched C 1 -6-alkyl which is optionally substituted by —NH—C(═O)—NH 2 , or represents aryl or benzyl which are optionally substituted by —NH 2 , 
 Y 5  is —H or —C(═O)—CHY 6 —NH 2 , and 
 Y 6  is straight-chain or branched C 1-6 -alkyl; 
 
         R 4  is —H, -L-#1, -SG lys -(C═O) 0-1 —R 4′ , —C(═O)—CHY 4 —NHY 5  or —(CH 2 ) 0-3 Z, wherein
 SG lys  is a group which can be cleaved by lysosomal enzymes, 
 wherein R 4′  is a C 1-10 -alkyl, C 5-10 -aryl or C 6-10 -aralkyl, C 5-10 -heteroalkyl, C 1-10 -alkyl-O—C 6-10 -aryl, C 5-10 -heterocycloalkyl, heteroaryl, heteroarylalkyl, heteroarylalkoxy, C 1-10 -alkoxy, C 6-10 -aryloxy or C 6-10 -aralkoxy,
 C 5-10 -heteroaralkoxy, C 1-10 -alkyl-O—C 6-10 -aryloxy, C 5-10 -heterocycloalkoxy group which may be mono- or polysubstituted by —NH 2 , —NH-alkyl, 
 —N(alkyl) 2 , —NH—C(═O)-alkyl, —N(alkyl)-C(═O)-alkyl, —SO 3 H, —S(═O) 2 —NH 2 , —S(═O) 2 —N(alkyl) 2 , —COOH, —C(═O)—NH 2 , —C(═O)—N(Alkyl) 2  or —OH, —H or a group —O x —(CH 2 CH 2 O) v —R 4″ , 
 wherein x is 0 or 1, 
 wherein v is a number from 1 to 20, 
 wherein R 4″  is —H, -alkyl,
 —CH 2 —COOH, —CH 2 —CH 2 —COOH, or —CH 2 —CH 2 —NH 2 ; 
 
 
 wherein Z is —H, halogen, —OY 3 , —SY 3 , —NHY 3 , —C(═O)—NY 1 Y 2  or —C(═O)—OY 3 ,
 wherein Y 1  and Y 2  are independently of one another —H, —NH 2  or —(CH 2 ) 0-3 Z′, 
 wherein Y 3  is —H or —(CH 2 ) 0-3 Z′, 
 wherein Z′ is —H, —SO 3 H, —NH 2  or —COOH; 
 wherein Y 4  is straight-chain or branched C 1-6 -alkyl which is optionally substituted by —NH—C(═O)—NH 2 , or represents aryl or benzyl which are optionally substituted by —NH 2 , 
 wherein Y 5  is —H or —C(═O)—CHY 6 —NH 2 , and 
 wherein Y 6  is straight-chain or branched C 1-6 -alkyl; 
 
 or 
 
         R 2  and R 4  taken together (with formation of a pyrrolidine ring) are —CH 2 —CHR 11 — or —CHR 11 —CH 2 —,
 wherein 
 
         R 11  is —H, —NH 2 , —SO 3 H, —COOH, —SH, halogen, C 1-4 -alkyl, C 1-4 -haloalkyl, C 1-4 -alkoxy, hydroxyl-substituted 
         C 1-4 -alkyl, C(═O)—O—(C 1-4 -alkyl) or —OH; 
         A is —C(═O)—, —S(═O)—, —S(═O) 2 —, —S(═O) 2 —NH— or —C(═N—NH 2 )—; 
         R 3  is -L-#1, -MOD or an optionally substituted alkyl, cycloalkyl, aryl, heteroaryl, heteroalkyl, or heterocycloalkyl group, 
         R 5  is —H, —NH 2 , —NO 2 , halogen, —CN, CF 3 , —OCF 3 , —CH 2 F, —CH 2 F, SH or —(CH 2 ) 0-3 Z, wherein
 Z is —H, —OY 3 , —SY 3 , halogen, —NHY 3 , —C(═O)—NY 1 Y 2  or —C(═O)—OY 3    
 Y 1  and Y 2  are independently of one another —H, —NH 2  or —(CH 2 ) 0-3 Z′, 
 Y 3  is —H or —(CH 2 ) 0-3 Z′, and 
 Z′ is —H, —SO 3 H, —NH 2  or —COOH; 
 
         R 6  and R 7  are independently of one another —H, cyano, C 1-10 -alkyl, fluoro-C 1-10 -alkyl, C 2-10 -alkenyl, fluoro-C 2-10 -alkenyl, C 2-10 -alkynyl, fluoro-C 2-10 -alkynyl, hydroxy, —NO 2 , —NH 2 , —COOH or halogen; 
         R 8  is C 1-10 -alkyl, fluoro-C 1-10 -alkyl, C 2-10 -alkenyl, fluoro-C 2-10 -alkyl, C 2-10 -alkynyl, fluoro-C 2-10 -alkynyl, C 4-10 -cycloalkyl, fluoro-C 4-10 -cycloalkyl or —(CH 2 ) 0-2 —(HZ 2 ), which may be mono- or disubstituted, identically or differently, by —OH, —COOH or —NH 2 , and
 wherein 
 HZ 2  is a 4- to 7-membered heterocycle having up to two heteroatoms selected from the group consisting of N, O and S; 
 
         R 9  is —H, —F, —CH 3 , —CF 3 , —CH 2 F or —CHF 2 ;
 wherein 
 one of the substituents R 1 , R 3  or R 4  is -L-#1, 
 
         L is the linker and #1 is the bond to the antibody, 
         MOD is —(NR 10 ) n -(G1) o -G2-G3,
 wherein 
 R 10  is —H or C 1 -C 3 -alkyl; 
 G1 is —NH—C(═O)— or —C(═O)—NH— (wherein, if G1 is —NH—C(═O)—, R 10  is not —NH 2 ); 
 n is 0 or 1; 
 o is 0 or 1; and 
 G2 is a straight-chain or branched hydrocarbon chain which has 1 to 10 carbon atoms and which may be interrupted once or more than once by one or more of the groups —O—, —S—, —S(═O)—, S(═O) 2 , —NR y —, —NR y C(═O)—, C(═O)—NR y —, —NR y NR y —, —S(═O) 2 —NR y NR y —, or —C(═O)—NR y NR y —
 wherein 
 R y  is —H, phenyl, C 1 -C 10 -alkyl, C 2 -C 10 -alkenyl or C 2 -C 0 o-alkynyl, each of which may be mono- or disubstituted, identically or differently, by —NH—C(═O)—NH 2 , —COOH, —OH, —NH 2 , —NH—CNNH 2 , sulphonamide, sulphone, sulphoxide or sulphonic acid,
 and/or which may be interrupted once or more than once, identically or differently, by —C(═O)—, —CR x ═N—O—, wherein 
 R x  is —H, C 1 -C 3 -alkyl or phenyl, and 
 
 wherein 
 the hydrocarbon chain including a C 1 -C 10 -alkyl group optionally substituted on the hydrocarbon group as side chain may be substituted by —NH—C(═O)NH 2 , —COOH, —OH, —NH 2 , —NH—CN—NH 2 , sulphonamide, sulphone, sulphoxide or sulphonic acid, G3 is —H or —COOH, and 
 wherein the group -MOD has at least one group —COOH; 
 
 
         or a salt, a solvate, a salt of a solvate, or an epimer thereof. 
       
     
     
       2. The conjugate according to  claim 1 , wherein A is —C(═O)—. 
     
     
       3. The conjugate according to  claim 1 , wherein R 1  is —H, -L-#1, —COOH, —C(═O)—NHNH 2 , —(CH 2 ) 1-3 NH 2 ,
 —C(═O)—NZ″(CH 2 ) 1-3  NH 2  or —C(═O)—NZ″CH 2 COOH, and wherein Z″ is —H or —NH 2 . 
 
     
     
       4. The conjugate according to  claim 1 , wherein
 R 2  and R 4  are —H; or 
 R 2  and R 4  together (with formation of a pyrrolidine ring) are —CHR 11 —CH 2 — or —CH 2 —CHR 11 —,
 wherein R 11  is —H, —COOH, —F, methyl, —CH 2 F, —O-methyl, —CH 2 OH, —C(═O)—O—(C 1-4 -alkyl) or —OH. 
 
 
     
     
       5. The conjugate according to  claim 1 , wherein
 R 3  is -L-#1; or 
 R 3  is a phenyl group which may be mono- or polysubstituted by halogen, C 1-3 -alkyl or fluoro-C 1-3 -alkyl; or 
 R 3  is a C 1-10 -alkyl group or fluoro-C1-10-alkyl group which may optionally be substituted by —OY 4 , —SY 4 , —O—C(═O)—Y 4 , —O—C(═O)—NH—Y 4 , —NH—C(═O)—Y 4 , —NH—C(═O)—NH—Y 4 , —S(O) n —Y 4 , —S(═O) 2 —NH—Y 4 , —NH—Y 4  or —N(Y 4 ) 2 ,
 wherein 
 n is 0, 1 or 2, and 
 Y 4  is —H, phenyl which is optionally mono- or polysubstituted by halogen, C 1-3 -alkyl or fluoro-C 1-3 -alkyl, or is alkyl which may be substituted by 
 —OH, —COOH and/or —NH—C(═O)—C 1-3 -alkyl. 
 
 
     
     
       6. The conjugate according to  claim 5 , wherein the conjugate has the formula (IIj) below: 
       
         
           
           
               
               
           
         
         wherein 
         R 3  is -L-#1; 
         A is —C(═O)—; and 
       
       R 6  and R 7  are independently of one another —H, cyano, C 1-10 -alkyl, fluoro-C 1-10 -alkyl, C 2-10 -alkenyl, fluoro-C 2-10 -alkenyl, C 2 -o-alkynyl, fluoro-C 2-10 -alkynyl, hydroxy, —NO 2 , —NH 2 , —COOH or halogen; 
       R 8  is C 1-10 -alkyl, fluoro-C 1-10 -alkyl, C 2-10 -alkenyl, fluoro-C 2-10 -alkyl, C 2-10 -alkynyl, fluoro-C 2-10 -alkynyl, C 4-10 -cycloalkyl, fluoro-C 4-10 -cycloalkyl or —(CH 2 ) 0-2 —(HZ 2 ), which may be mono- or disubstituted, identically or differently, by —OH, —COOH or —NH 2 ,
 wherein 
 HZ 2  is a 4- to 7-membered heterocycle having up to two heteroatoms selected from the group consisting of N, O and S; and 
 
       R 9  is —H, —F, —CH 3 , —CF 3 , —CH 2 F or —CHF 2 . 
     
     
       7. The conjugate according to  claim 1 , wherein the substituent R 1  is -L-#1. 
     
     
       8. The conjugate according to  claim 7 , where the conjugate has the formula (IIk): 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is -L-#1; 
         A is —C(═O)—; 
         R 3  is —CH 2 OH; 
       
       R 6  and R 7  are independently of one another —H, cyano, C 1-10 -alkyl, fluoro-C 1-10 -alkyl, C 2-10 -alkenyl, fluoro-C 2-10 -alkenyl, C 2-10 -alkynyl, fluoro-C 2-10 -alkynyl, hydroxy, —NO 2 , —NH 2 , —COOH or halogen, 
       R 8  is C 1-10 -alkyl, fluoro-C 1-10 -alkyl, C 2-10 -alkenyl, fluoro-C 2-10 -alkyl, C 2-10 -alkynyl, fluoro-C 2-10 -alkynyl, C 4-10 -cycloalkyl, fluoro-C 4-10 -cycloalkyl or —(CH 2 ) 0-2 —(HZ 2 ), which may be mono- or disubstituted, identically or differently, by —OH, —COOH or —NH 2 ,
 wherein 
 HZ 2  is a 4- to 7-membered heterocycle having up to two heteroatoms selected from the group consisting of N, O and S; and 
 
       R 9  is —H, —F, —CH 3 , —CF 3 , —CH 2 F or —CHF 2 . 
     
     
       9. The conjugate according to  claim 1 , wherein R 5  is —H or —F. 
     
     
       10. The conjugate according to  claim 1 , wherein R 6  and R 7  are independently of one another —H, C 1-3 -alkyl, fluoro-C 1-3 -alkyl, C 2-4 -alkenyl, fluoro-C 2-4 -alkenyl, C 2-4 -alkynyl, fluoro-C 2-4 -alkynyl, hydroxy or halogen. 
     
     
       11. The conjugate according to  claim 1 , wherein R 8  is a branched C 1 -s-alkyl group or cyclohexyl. 
     
     
       12. The conjugate according to  claim 1 , wherein R 9  is —H or fluorine. 
     
     
       13. The conjugate according to  claim 1 , wherein the linker -L- has one of the basic structures (i) to (iv) below:
   —(CO) m -SG1-L1-L2;-  (i)
 
   —(CO) m -L1-SG-L1-L2-;  (ii)
 
   —(CO) m -L1-L2-; or  (iii)
 
   —(CO) m -L1-SG-L2;  (iv)
 
 
       wherein 
       m is 0 or 1; 
       SG and SG1 are in vivo cleavable groups; 
       each L1 is independently of one another an organic group not cleavable in vivo; 
       and 
       L2 is a coupling group to the binder. 
     
     
       14. The conjugate according to  claim 13 , wherein the in vivo cleavable group SG is a 2-8 oligopeptide group, or a disulphide, a hydrazone, an acetal or an aminal; and SG1 is a 2-8 oligopeptide group. 
     
     
       15. The conjugate according to  claim 1 ,
 wherein the linker L is attached to a cysteine side chain or a cysteine residue and has the formula below:
   § —(C(═O)-) m -L1-L2- § §
 
 
 
       wherein 
       m is 0 or 1; 
       § is the bond to the active compound molecule; 
       § § is the bond to the antibody; 
       -L2-is 
       
         
           
           
               
               
           
         
         wherein 
       
       # 1  denotes the point of attachment to the sulphur atom of the antibody; 
       # 2  denotes the point of attachment to group L1; 
       L 1  is —(NR 10 ) n -(G1)o-G2-,
 wherein 
 R 10  is —H, —NH 2  or C 1 -C 3 -alkyl; 
 G1 is —NH—C(═O)—; 
 n is 0 or 1; 
 o is 0 or 1; and 
 G2 is a straight-chain or branched hydrocarbon chain having 1 to 100 carbon atoms from aryl groups, and/or straight-chain and/or branched alkyl groups, and/or cyclic alkyl groups and which may be interrupted once or more than once, identically or differently by —O—, —S—, —S(═O)—, S(═O) 2 —, —NH—, —C(═O)—, —N—CH 3 —, —NHNH—, —S(═O) 2 —NHNH—, —NH—C(═O)—, —C(═O)—NH—, —C(═O)—NHNH— and a 5- to 10-membered aromatic or non-aromatic heterocycle having 1 to 4 identical or different heteroatoms and/or hetero groups selected from N, O and S, —S(═O)— or —S(═O) 2 —, 
 where the straight-chain or branched hydrocarbon chain may optionally be substituted by —NH—C(═O)—NH 2 , —COOH, —OH, —NH 2 , —NH—CNNH 2 , sulphonamide, sulphone, sulphoxide or sulphonic acid, 
 or represents one of the groups below: 
 
       
         
           
           
               
               
           
         
         wherein R x  is —H, C 1 -C 3 -alkyl or phenyl. 
       
     
     
       16. The conjugate according to  claim 15 , wherein L2 is represented by one or both of the formulae below: 
       
         
           
           
               
               
           
         
         wherein 
         # 1  denotes the point of attachment to the sulphur atom of the binder; 
         # 2  denotes the point of attachment to group L; 
         R 22  is —COOH; and 
         wherein more than 80% (based on the total number of bonds of the linker to the binder) of the bonds to the sulphur atom of the binder are present in one of these two structures. 
       
     
     
       17. The conjugate according to  claim 15 , wherein L has the formulae below: 
       
         
           
           
               
               
           
         
       
       wherein 
       r is a number from 0 to 8. 
     
     
       18. The conjugate according to  claim 1 , wherein the linker -L- is attached to a cysteine side chain or a cysteine residue and has the formula below: 
       
         
           
           
               
               
           
         
         wherein 
         § is the bond to the active compound molecule; 
         § § is the bond to the antibody; 
         m is 0, 1, 2 or 3; 
         n is 0, 1 or 2; 
         p is 0 to 20; and 
         L3 is 
       
       
         
           
           
               
               
           
         
         wherein 
         o is 0 or 1; and 
         G3 is a straight-chain or branched hydrocarbon chain having 1 to 100 carbon atoms from aryl groups, and/or straight-chain and/or branched alkyl groups, and/or cyclic alkyl groups and which may be interrupted once or more than once, identically of differently by —O—, —S—, —S(═O)—, S(═O) 2 —, —NH—, —C(═O)—, —N—CH 3 —, —NHNH—, —S(═O) 2 —NHNH—, —NH—C(═O)—, —C(═O)—NH—, —C(═O)—NHNH— and a 5- to 10-membered aromatic or non-aromatic heterocycle having 1 to 4 identical or different heteroatoms and/or hetero groups selected from N, O and S, —S(═O)— or —S(═O) 2 —, 
         where the straight-chain or branched hydrocarbon chain may optionally be substituted by —NH—C(═O)—NH 2 , —COOH, —OH, —NH 2 —, —NH—CN—NH 2 , sulphonamide, sulphone, sulphoxide or sulphonic acid. 
       
     
     
       19. The conjugate according to  claim 1 , wherein the conjugate has one of the formulae below: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein 
         AK1 is an anti-CD123 antibody attached via cysteine and AK2 is an anti-CD123 antibody attached via lysine, which antibody is a chimeric or humanized variant of the antibody 7G3 or 12F1; 
         n is a number from 1 to 20; and 
         L 1  is a straight-chain or branched hydrocarbon chain having 1 to 30 carbon atoms which may be interrupted once or more than once, identically or differently, by —O—, —S—, —C(═O)—, —S(═O) 2 —, —NH—, cyclopentyl, piperidinyl, or phenyl,
 wherein the straight-chain or branched hydrocarbon chain may be substituted by —COOH or —NH 2 , 
 
         or a salt, a solvate, a salt of a solvate, or an epimer thereof. 
       
     
     
       20. The conjugate according to  claim 19 , wherein the linker L 1  is the group
 § —NH—(CH 2 ) 2 —§ §; 
 § —NH—(CH 2 ) 6 —§ §; 
 § —NH—(CH 2 ) 2 —O—(CH 2 ) 2 —§ §; 
 § —NH—CH(COOH)—(CH 2 ) 4 —§ § 
 § —NH—NH—C(═O)—(CH 2 ) 5 —§ §; 
 § —NH—(CH 2 ) 2 —C(═O)—O—(CH 2 ) 2 —§ §; 
 § —NH—(CH 2 ) 2 —C(═O)—NH—(CH 2 ) 2 —§ §; 
 § —NH—(CH 2 ) 2 —NH—C(═O)—CH 2 —§ §; 
 § —NH—(CH 2 ) 3 —NH—C(═O)—CH 2 —§ §; 
 § —NH—(CH 2 ) 2 —NH—C(═O)—(CH 2 ) 2 —§ §; 
 § —NH—(CH 2 ) 2 —NH—C(═O)—(CH 2 ) 5 —§ §; 
 § —NH—(CH 2 ) 2 —NH—C(═O)—CH(CH 3 )—§ §; 
 § —NH—(CH 2 ) 2 —O—(CH 2 ) 2 —NH—C(═O)—CH 2 —§ §; 
 § —NH—CH(COOH)—CH 2 —NH—C(═O)—CH 2 —§ §; 
 § —NH—CH(COOH)—(CH 2 ) 2 —NH—C(═O)—CH 2 —§ §; 
 § —NH—CH(COOH)—(CH 2 ) 4 —NH—C(═O)—CH 2 —§ §; 
 § —NH—CH(COOH)—CH 2 —NH—C(═O)—(CH 2 ) 2 —§ §; 
 § —NH—(CH 2 ) 2 —NH—C(═O)—CH(C 2 H 4 COOH)—§ §; 
 § —NH—(CH 2 ) 2 —NH—C(═O)—((CH 2 ) 2 —O) 3 —(CH 2 ) 2 —§ §; 
 § —NH—(CH 2 ) 2 —S(═O) 2 —(CH 2 ) 2 —NH—C(═O)—CH 2 —§ §; 
 § —NH—(CH 2 ) 2 —NH—C(═O)—CH 2 —NH—C(═O)—CH 2 —§ §; 
 § —NH—(CH 2 ) 3 —NH—C(═O)—CH 2 —NH—C(═O)—CH 2 —§ §; 
 § —NH—CH(COOH)—CH 2 —NH—C(═O)—CH(CH 2 COOH)—§ §; 
 § —NH—(CH 2 ) 2 —NH—C(═O)—CH(C 2 H 4 COOH)—NH—C(═O)—CH 2 —§ §; 
 § —NH—CH(COOH)—CH 2 —NH—C(═O)—(CH 2 ) 2 —NH—C(═O)—CH 2 —§ §; 
 § —NH—(CH 2 ) 2 —NH—C(═O)—(CH 2 ) 2 —CH(COOH)—NH—C(═O)—CH 2 —§ §; 
 § —NH—CH(COOH)—CH 2 —NH—C(═O)—CH(CH 2 OH)—NH—C(═O)—CH 2 —§ §; 
 § —NH—CH [C(═O)—NH—(CH 2 ) 2 —O) 4 —(CH 2 ) 2 COOH]—CH 2 —NH—C(═O)—CH 2 —§ §; 
 § —NH—CH(COOH)—CH 2 —NH—C(═O)—((CH 2 ) 2 —O) 4 —(CH 2 ) 2 —NH—C(═O)—CH 2 —§ §; 
 § —NH—(CH 2 ) 4 —CH(COOH)—NH—C(═O)—CH(CH 3 )—NH—C(═O)—CH(isoC 3 H 7 )—§ §; 
 § —NH—(CH 2 ) 4 —CH(COOH)—NH—C(═O)—CH(CH 3 )—NH—C(═O)—CH(isoC 3 H 7 )—NH—C(═O)—(CH 2 ) 5 —§ §; 
 § —NH—(CH 2 ) 2 —C(═O)—NH—(CH 2 ) 4 —CH(COOH)—NH—C(═O)—CH(CH 3 )—NH—C(═O)—CH(isoC 3 H 7 )—NH—C(═O)—CH 2 —§ §; 
 § —NH—(CH 2 ) 2 —C(═O)—NH—(CH 2 ) 4 —CH(COOH)—NH—C(═O)—CH(CH 3 )—NH—C(═O)—CH(isoC 3 H 7 )—NH—C(═O)—(CH 2 ) 5 —§ §; 
 § —NH—(CH 2 ) 4 —CH(COOH)—NH—C(═O)— CH[(CH 2 ) 3 —NH—C(═O)—NH 2 ]—NH—C(═O)—CH(isoC 3 H 7 )—NH—C(═O)—(CH 2 ) 5 —§ §; 
 § —NH—(CH 2 ) 2 —NH—C(═O)—(CH 2 ) 2 —CH(COOH)—NH—C(═O)—CH(CH 3 )—NH—C(═O)—CH(isoC 3 H 7 )—NH—C(═O)—(CH 2 ) 5 —§ §; 
 § —NH—CH(CH 3 )—C(═O)—NH—(CH 2 ) 4 —CH(COOH)—NH—C(═O)—CH(CH 3 )—NH—C(═O)—CH(isoC 3 H 7 )—NH—C(═O)—(CH 2 ) 5 —§ §; 
 § —NH—(CH 2 ) 2 —C(═O)—NH—(CH 2 ) 4 —CH(COOH)—NH—C(═O)—CH[(CH 2 ) 3 —NH—C(═O)—NH 2 ]—NH—C(═O)—CH(isoC 3 H 7 )—NH—C(═O)—(CH 2 ) 5 —§ §; 
 
       
         
           
           
               
               
           
         
         § —(CH 2 ) 2 —C(═O)—NH—(CH 2 ) 2 —§ §; 
         § —(CH 2 ) 2 —C(═O)—NH—(CH 2 ) 2 —NH—C(═O)—CH 2 —§ §; 
         § —CH(CH 3 )—NH—C(═O)—CH(isoC 3 H 7 )—§ §; 
         § —CH(CH 3 )—NH—C(═O)—CH(isoC 3 H 7 )—NH—C(═O)—CH 2 —§ §; 
         § —CH(CH 3 )—NH—C(═O)—CH(isoC 3 H 7 )—NH—C(═O)—(CH 2 ) 5 —§ §; 
         § —(CH 2 ) 2 —C(═O)—NH—((CH 2 ) 2 —O) 4 —(CH 2 ) 2 —NH—C(═O)—CH 2 —§ §; 
         § —CH(CH 3 )—NH—C(═O)—CH(isoC 3 H 7 )—NH—C(═O)—((CH 2 ) 2 —O) 4 —(CH 2 ) 2 —NH—C(═O)—(CH 2 ) 2 —§ §; 
       
       
         
           
           
               
               
           
         
         § —CH 2 —S—(CH 2 ) 2 —C(═O)—NH—(CH 2 ) 2 —§ §; 
         § —CH 2 —S—(CH 2 ) 5 —C(═O)—NH—(CH 2 ) 2 —§ §; 
         § —CH 2 —S—CH 2 CH(COOH)—NH—C(═O)—CH 2 —§ §; 
         § —CH 2 —S—CH 2 CH(COOH)—NH—C(═O)—(CH 2 ) 5 —§ §; 
         § —CH 2 —S—(CH 2 ) 2 —C(═O)—NH—((CH 2 ) 2 —O) 2 —(CH 2 ) 2 —§ §; 
         § —CH 2 —S—(CH 2 ) 2 —C(═O)—NH—((CH 2 ) 2 —O) 2 —(CH 2 ) 5 —§ §; 
         § —CH 2 —S—(CH 2 ) 2 —C(═O)—NH—(CH 2 ) 2 —NH—C(═O)—CH 2 —§ §; 
         § —CH 2 —S—(CH 2 ) 2 —C(═O)—NH—(CH 2 ) 2 —NH—C(═O)—CH 5 —§ §; 
         § —CH 2 —S—(CH 2 ) 2 —C(═O)—NH—CH(COOH)—CH 2 —NH—C(═O)—CH 2 —§ §; 
         § —CH 2 —S—CH 2 CH(NH 2 )—C(═O)—NH—(CH 2 ) 2 —NH—C(═O)—(CH 2 ) 5 —§ §; 
         § —CH 2 —S—(CH 2 ) 2 —C(═O)—NH—((CH 2 ) 2 —O) 2 —(CH 2 ) 2 —NH—C(═O)—CH 2 —§ §; 
         § —CH 2 —S—(CH 2 ) 2 —C(═O)—NH—((CH 2 ) 2 —O) 4 —(CH 2 ) 2 —NH—C(═O)—CH 2 —§ §; 
         § —CH 2 —S—(CH 2 ) 2 —C(═O)—NH—((CH 2 ) 2 —O) 2 —(CH 2 ) 2 —NH—C(═O)—(CH 2 ) 5 —§ §; 
         § —CH 2 —S—(CH 2 ) 2 —C(═O)—NH—((CH 2 ) 2 —O) 4 —(CH 2 ) 2 —NH—C(═O)—(CH 2 ) 5 —§ §; 
         § —CH 2 —S—CH 2 CH(COOH)—NH—C(═O)—((CH 2 ) 2 —O) 2 —(CH 2 ) 2 —NH—C(═O)—CH 2 —§ §; 
         § —CH 2 —S—CH 2 CH(COOH)—NH—C(═O)—((CH 2 ) 2 —O) 4 —(CH 2 ) 2 —NH—C(═O)—CH 2 —§ §; 
         § —CH 2 —S—CH 2 CH(COOH)—NH—C(═O)—((CH 2 ) 2 —O) 4 —(CH 2 ) 2 —NH—C(═O)—(CH 2 ) 2 —§ §; 
         § —CH 2 —S—(CH 2 ) 2 —CH(COOH)—NH—C(═O)—((CH 2 ) 2 —O) 4 —(CH 2 ) 2 —NH—C(═O)—(CH 2 ) 2 —§§; 
         § —CH 2 —S—(CH 2 ) 2 —C(═O)—NH—CH(C 2 H 4 COOH)—C(═O)—NH—(CH 2 ) 2 —NH—C(═O)—CH 2 —§ §; 
         § —CH 2 —S—CH 2 CH[NH—C(═O)—(CH 2 ) 2 —COOH]—C(═O)—NH—(CH 2 ) 2 —NH—C(═O)—CH 2 —§§; 
         § —CH 2 —S—CH 2 CH[NH—C(═O)—((CH 2 ) 2 —O) 4 —CH 3 ]—C(═O)—NH—(CH 2 ) 2 —NH—C(═O)—CH 2 —§ §; 
         § —CH 2 —S—CH 2 CH(COOH)—NH—C(═O)—CH(CH 3 )—NH—C(═O)—CH(isoC 3 H 7 )—NH—C(═O)—CH 2 —§ §; 
         § —CH 2 —S—CH 2 CH[NH—C(═O)—(CH 2 ) 2 —COOH]—C(═O)—NH—(CH 2 ) 2 —S(═O) 2 —(CH 2 ) 2 —NH—C(═O)—CH 2 —§ §; 
         § —CH 2 —S—CH 2 CH[NH—C(═O)—(CH 2 ) 2 —COOH]—C(═O)—NH—((CH 2 ) 2 —O) 4 —(CH 2 ) 2 —NH—C(═O)—CH 2 —§ §; 
         § —CH 2 —S—CH 2 CH[C(═O)—NH—(CH 2 ) 2 —COOH]—NH—C(═O)—((CH 2 ) 2 —O) 4 —(CH 2 ) 2 —NH—C(═O)—CH 2 —§ §; 
         § —CH 2 —S—CH 2 CH[C(═O)—NH—(CH 2 ) 2 —COOH]—NH—C(═O)—((CH 2 ) 2 —O) 4 —(CH 2 ) 2 —NH—C(═O)—(CH 2 ) 2 —§ §; 
         § —CH 2 —S—CH 2 CH(COOH)—NH—C(═O)—(CH 2 ) 2 CH(COOH)—NH—C(═O)—((CH 2 ) 2 —O) 4 —(CH 2 ) 2 —NH—C(═O)—CH 2 —§ § 
         § —CH 2 —S—CH 2 CH[C(═O)—NH—((CH 2 ) 2 —O) 4 —(CH 2 ) 2 —COOH]—NH—C(═O)—((CH 2 ) 2 —O) 4 —(CH 2 ) 2 —NH—C(═O)—CH 2 —§ §; 
         or 
         § —CH 2 —S—CH 2 CH(COOH)—NH—C(═O)—CH[(CH 2 ) 2 —COOH]—NH—C(═O)—((CH 2 ) 2 —O) 4 —(CH 2 ) 2 —NH—C(═O)—(CH 2 ) 2 —§ §, 
         wherein 
         § is the bond to the active compound molecule; 
         § § is the bond to the antibody; and 
         isoC 3 H 7  is an isopropyl radical, 
         or a salt, a solvate, a salt of a solvate, or an epimer thereof. 
       
     
     
       21. The conjugate according to  claim 1 , wherein the conjugate has one of the formulae below: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein 
         AK1 is an anti-CD123 antibody attached via cysteine and AK2 is an anti-CD123 antibody attached via lysine, which antibody is a chimeric or humanized variant of the antibody 7G3 or 12F1, and 
         n is a number from 1 to 20. 
       
     
     
       22. The conjugate according to  claim 1 , wherein the anti-CD123 antibody or an antigen-binding fragment thereof comprises:
 a variable heavy chain comprising the variable CDR1 sequence of the heavy chain, as shown in SEQ ID NO: 2, the variable CDR2 sequence of the heavy chain, as shown in SEQ ID NO: 3, and the variable CDR3 sequence of the heavy chain, as shown in SEQ ID NO: 4, and 
 a variable light chain comprising the variable CDR1 sequence of the light chain, as shown in SEQ ID NO: 6, the variable CDR2 sequence of the light chain, as shown in SEQ ID NO: 7, and the variable CDR3 sequence of the light chain, as shown in SEQ ID NO: 8; or 
 a variable heavy chain comprising the variable CDR1 sequence of the heavy chain, as shown in SEQ ID NO: 12, the variable CDR2 sequence of the heavy chain, as shown in SEQ ID NO: 13, and the variable CDR3 sequence of the heavy chain, as shown in SEQ ID NO: 14, and 
 a variable light chain comprising the variable CDR1 sequence of the light chain, as shown in SEQ ID NO: 16, the variable CDR2 sequence of the light chain, as shown in SEQ ID NO: 17, and the variable CDR3 sequence of the light chain, as shown in SEQ ID NO: 18; or 
 a variable heavy chain comprising the variable CDR1 sequence of the heavy chain, as shown in SEQ ID NO: 22, the variable CDR2 sequence of the heavy chain, as shown in SEQ ID NO: 23, and the variable CDR3 sequence of the heavy chain, as shown in SEQ ID NO: 24, and 
 a variable light chain comprising the variable CDR1 sequence of the light chain, as shown in SEQ ID NO: 26, the variable CDR2 sequence of the light chain, as shown in SEQ ID NO: 27, and the variable CDR3 sequence of the light chain, as shown in SEQ ID NO: 28; or 
 a variable heavy chain comprising the variable CDR1 sequence of the heavy chain, as shown in SEQ ID NO: 32, the variable CDR2 sequence of the heavy chain, as shown in SEQ ID NO: 33, and the variable CDR3 sequence of the heavy chain, as shown in SEQ ID NO: 34, and 
 a variable light chain comprising the variable CDR1 sequence of the light chain, as shown in SEQ ID NO: 36, the variable CDR2 sequence of the light chain, as shown in SEQ ID NO: 37, and the variable CDR3 sequence of the light chain, as shown in SEQ ID NO: 38. 
 
     
     
       23. The conjugate according to  claim 1 , wherein the anti-CD123 antibody or an antigen-binding fragment thereof comprises:
 a variable sequence of the heavy chain, as shown in SEQ ID NO:1, and also a variable sequence of the light chain, as shown in SEQ ID NO:5; or 
 a variable sequence of the heavy chain, as shown in SEQ ID NO:11, and also a variable sequence of the light chain, as shown in SEQ ID NO: 15; or 
 a variable sequence of the heavy chain, as shown in SEQ ID NO:21, and also a variable sequence of the light chain, as shown in SEQ ID NO:25; or 
 a variable sequence of the heavy chain, as shown in SEQ ID NO:31, and also a variable sequence of the light chain, as shown in SEQ ID NO:35. 
 
     
     
       24. The conjugate according to  claim 1 , wherein the anti-CD123 antibody is an IgG antibody. 
     
     
       25. The conjugate according to  claim 1 , wherein the anti-CD123 antibody comprises:
 a sequence of the heavy chain, as shown in SEQ ID NO:9, and also a sequence of the light chain, as shown in SEQ ID NO:10; or 
 a sequence of the heavy chain, as shown in SEQ ID NO: 19, and also a sequence of the light chain, as shown in SEQ ID NO:20; or 
 a sequence of the heavy chain, as shown in SEQ ID NO:29, and also a sequence of the light chain, as shown in SEQ ID NO:30; or 
 a sequence of the heavy chain, as shown in SEQ ID NO:39, and also a sequence of the light chain, as shown in SEQ ID NO:40. 
 
     
     
       26. A pharmaceutical composition comprising a conjugate according to  claim 1 , in combination with an inert non-toxic pharmaceutically suitable auxiliary. 
     
     
       27. A method for treatment of lung cancer, leukemia, myeloma, Hodgkin's lymphoma or breast cancer, comprising administering to a patient in need thereof a conjugate according to  claim 1 . 
     
     
       28. The conjugate of  claim 1 , wherein R 3  is -L-#1 or a C 1-10 -alkyl, C 6-10 -aryl or C 6-10 -aralkyl, C 5-10 -heteroalkyl, C 1-10 -alkyl-O—C 6-10 -aryl or C 5-10 -heterocycloalkyl group which may in each case be substituted by 1-3-OH groups, 1-3 halogen atoms, 1-3 halogenated alkyl groups (each having 1-3 halogen atoms), 1-3-O-alkyl groups, 1-3-SH groups, 1-3-S-alkyl groups, 1-3-O—C(═O)-alkyl groups, 1-3-O—C(═O)—NH-alkyl groups, 1-3-NH—C(═O)-alkyl groups, 1-3-NH—C(═O)—NH-alkyl groups, 1-3-S(═O) n -alkyl groups, 1-3-S(═O) 2 —NH-alkyl groups, 1-3-NH-alkyl groups, 1-3-N(alkyl) 2  groups, 1-3-NH 2  groups or 1-3-(CH 2 ) 0-3 Z groups,
 wherein 
 n is 0, 1 or 2, 
 Z is —H, halogen, —OY 3 , —SY 3 , —NHY 3 , —C(═O)—NY 1 Y 2  or —C(═O)—OY 3 , 
 Y 1  and Y 2  are independently of one another —H, —NH 2  or —(CH 2 ) 0-3 Z′ 
 Y 3  is —H, —(CH 2 ) 0-3 —CH(NH—C(═O)—CH 3 )Z′, —(CH 2 ) 0-3 —CH(NH 2 )Z′ or —(CH 2 ) 0-3 Z′, and 
 Z′ is —H, —SO 3 H, —NH 2  or —COOH.